Combined risk scores of genetic variants of lipid levels have added predictive value for CV disease
Risk scores of common genetic variants for lipid levels influence atherosclerosis and incident coronary heart disease.
Isaacs A, Willems SM, Bos D et al.
Arterioscler Thromb Vasc Biol. 2013 Sep;33(9):2233-9. doi: 10.1161/ATVBAHA.113.301236
BackgroundHeritability estimates for lipid levels are moderate to high [1,2], and genome-wide association studies (GWAS) have identified many genetics variants that contribute to interindividual differences in circulating lipid levels [3-6].
95 genetic loci have been identified by the Global Lipid Genetics Consortium (GLGC) that contain single nucleotide polymorphisms (SNPs) that are associated with one or more blood lipid measurements . These SNPs can be used to determine LDL-c, HDL-c and triglyceride (TG) risk scores, with which individuals with extreme lipid values can be discriminated from low-lipid controls.
Only few of the 95 genetic loci were associated with coronary artery disease , possibly because each of the individual genetic loci only has a small effect. This study tested the hypothesis that cumulative effects of common genetic lipid variants are associated with subclinical atherosclerosis and incident coronary heart disease (CHD). Data were used from the Rotterdam Study (RS, n=8130) and the Erasmus Rucphen Family (ERF, n=2269). 4 risk scores were computed from different SNPs: total cholesterol (TC), LDL-C, HDL-C and TG risk.
- TC and LDL-c scores were robustly associated with carotid plaque score in both cohorts separately, and in a meta-analysis that combined all data, while weaker associations were seen between TC and LDL-c risk scores and carotid intima-media thickness (IMT). The HDL-c risk score was mildly associated with plaque, but not with IMT.
- Lipid levels corresponding to the genetic risk scores were added to the statistical models that showed significant associations between the risk scores and IMT or plaque. Effect estimates for the risk scores were lower, but still significant.
- TC and LDL-c scores were also associated with MI and CHD. No associations were seen for HDL-c and TG risk scores with either incident MI or CHD. Adding TC levels to the models that assessed the association of the TC genetic risk score with MI and CHD yielded lower HRs that were still borderline significant, while adding LDL-c did not affect the HRs.
- The Framingham Risk Scores (FRS) predicted incident MI and CHD better in the RS than the genetic risk scores combined (based on AUCs). Combining the genetic risk scores with FRS only slightly improved the predictive value for MI of FRS alone, while for CHD predictive value was not improved.
ConclusionCombinations of common genetic variants associated with TC, LDL-c, HDL-c and TG, each with small effects on lipid levels, are significantly associated with the development of subclinical and clinical cardiovascular outcomes. The observation that the genetic risk scores were still associated with plaques after inclusion of lipid levels into the model, suggests that the genetic risk scores have some added value beyond the lipid levels themselves, although genetic risk scores did not improve clinical AUCs. With advancing knowledge on genetic variation, preclinical genetic screening tools may be beneficial in predicting and preventing clinical events by detecting individuals at high risk for CVD.
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